1. Mok TS, Wu SL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957 Gefitinib Superior to Carboplatin/ Paclitaxel as First-line Therapy in Pulmonary Adenocarcinoma This program is supported by an educational grant from

2. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC  Gefitinib: oral EGFR tyrosine kinase inhibitor  Gefitinib more efficacious than chemotherapy in previously treated NSCLC [1]  EGFR mutation correlated with higher response rate to gefitinib [2]  IPASS trial conducted in East Asia compared gefitinib with carboplatin plus paclitaxel as first-line treatment in Asian nonsmokers or former light-smokers with advanced pulmonary adenocarcinoma –Evaluated efficacy, safety, tolerability 1. Kim ES, et al. Lancet. 2008;372:1809-1818. 2. Hirsch FR, et al. J Clin Oncol. 2006;24:5034-5042. Background

3. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Previously untreated NSCLC patients (N = 1217) Up to six 3-wk cycles Gefitinib 250 mg/day PO (n = 609) Paclitaxel 200 mg/m 2 IV on Day 1 + Carboplatin AUC 5-6 mg/mL/min IV on Day 1 (n = 608) Mok TS, et al. N Engl J Med. 2009;361:247-257. IPASS Study Design

4. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Eligibility  18 yrs of age or older  Histologically or cytologically confirmed stage IIIB or IV NSCLC with adenocarcinoma histology  Nonsmoker (< 100 cigarettes in lifetime) or former light-smoker (≤ 10 pack-yrs in lifetime, none within previous 15 yrs)  No previous chemotherapy  WHO performance score 0-2  Measurable disease by RECIST criteria  Absolute neutrophil count: > 2.0 x 10 9 /L  Adequate hepatic function Mok TS, et al. N Engl J Med. 2009;361:247-257.

5. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC CharacteristicGefitinib (n = 609) Paclitaxel/Carboplatin (n = 608) Female, %79.579.1 Median age, yrs (range)57 (24-84)57 (25-84) Smoking history, %  Nonsmoker  Former light smoker 93.8 6.1 93.6 6.2 WHO PS, %  0  1  2 25.8 64.2 10.0 26.5 62.8 10.7 Disease stage at entry, %  IIIB  IV  Unknown 24.6 75.4 0 23.7 76.2 0.2 Mok TS, et al. N Engl J Med. 2009;361:247-257. Baseline Characteristics

6. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC EGFR Mutation Status, %Gefitinib (n = 609) Paclitaxel/Carboplatin (n = 608)  Negative14.914.0  Positive Exon 19 deletion* Exon 21 L858R* Exon 20 T790M* Other* 21.7 10.8 10.5 0.8 0.5 21.2 12.2 7.7 1.0 1.2  Unknown63.464.8 *11 patients had multiple EGFR mutations and are counted for each mutation present. Mok TS, et al. N Engl J Med. 2009;361:247-257. Baseline Characteristics: EGFR Status

7. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Current Analysis  Intent to treat  Primary endpoint: PFS  Secondary endpoints –OS –ORR –Quality of life –Symptom reduction –Safety –AE profile  Planned exploratory analysis of efficacy according to EGFR mutation status Mok TS, et al. N Engl J Med. 2009;361:247-257.

8. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Main Findings: Progression-Free Survival  Significantly longer PFS with gefitinib (P <.001) –12-mo PFS: 24.9% with gefitinib vs 6.7% with chemotherapy –PFS superior with carboplatin/paclitaxel for first 6 mos but superior with gefitinib after 6 mos –Median PFS: 5.7 mos with gefitinib vs 5.8 mos with paclitaxel/carboplatin –Kaplan-Meier curves cross near median PFS Mok TS, et al. N Engl J Med. 2009;361:247-257.

9. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Main Findings: Significance of EGFR Mutation Status  Significant interaction between treatment and EGFR mutation status –In EGFR mutation–positive subgroup, significantly longer PFS with gefitinib (HR: 0.48; 95% CI: 0.36-0.64; P <.001) –In EGFR mutation–negative subgroup, significantly shorter PFS with gefitinib (HR: 2.85; 95% CI: 2.05-3.98; P <.001) Mok TS, et al. N Engl J Med. 2009;361:247-257. Reproduced with permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. EGFR Mutation Positive HR: 0.48 (95% CI: 0.36-0.64; P <.001) Probability of PFS Mos Since Randomization Gefitinib Paclitaxel/ carboplatin 1.0 0.8 0.6 0.4 0.2 0 04812162024 EGFR Mutation Negative HR: 2.85 (95% CI: 2.05-3.98; P <.001) Probability of PFS Mos Since Randomization Gefitinib Paclitaxel/ carboplatin 1.0 0.8 0.6 0.4 0.2 0 04812162024 Events Gefitinib: 97 (73.5%) Pac/carbo: 111 (86.0%) Events Gefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%)

10. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Main Findings: Response Rates  Significantly higher ORR with gefitinib than carboplatin- paclitaxel –Driven by EGFR mutation–positive subgroup  Significantly higher quality of life improvements with gefitinib than paclitaxel/carboplatin  Rates of symptom reduction similar between arms ORR, %GefitinibPaclitaxel/ Carboplatin P Value Overall population43.032.2<.001 EGFR mutation positive71.247.3<.001 EGFR wild type1.123.5.001 Mok TS, et al. N Engl J Med. 2009;361:247-257.

11. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Main Findings: Toxicities  Gefitinib associated with acceptable toxicity profile –AEs more common with gefitinib: rash or acne, diarrhea, elevated liver enzymes –AEs more common with carboplatin/paclitaxel: neurotoxicity, nausea and vomiting, hematologic toxicity Incidence, % Gefitinib (n = 609) Paclitaxel/Carboplatin (n = 608) Any grade 3/4 AE28.761.0 AE leading to discontinuation6.913.6 AE leading to dose modification16.1 35.2 (carboplatin) 37.5 (paclitaxel) Serious AE, including death16.315.6 Mok TS, et al. N Engl J Med. 2009;361:247-257.

12. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Other Outcomes  OS similar between arms in preliminary analysis –Median OS: 18.6 mos with gefitinib vs 17.3 mos with paclitaxel/carboplatin –Gefitinib-treated EGFR mutation–positive subgroup –HR: 0.78 (95% CI: 0.50-1.20) –Gefitinib-treated EGFR mutation–negative subgroup –HR: 1.38 (95% CI: 0.92-2.09)  Ongoing analysis of OS  Response rate to both gefitinib and paclitaxel/carboplatin better in EGFR mutation-positive vs EGFR mutation-negative patients Mok TS, et al. N Engl J Med. 2009;361:247-257.

13. clinicaloptions.com/oncology Practice in Evolution: Optimal Management of NSCLC Summary of Key Conclusions  Gefitinib superior to paclitaxel/carboplatin chemotherapy as first-line treatment in Asian pulmonary adenocarcinoma patients who were nonsmokers or former light smokers  Longer PFS, higher ORR, reduced toxicity, and improved quality of life with gefitinib vs carboplatin/paclitaxel  Overall benefit with gefitinib driven by EGFR mutation– positive patient subgroup –EGFR mutation–negative patients have poorer PFS and ORR with gefitinib compared with chemotherapy –EGFR mutation status predictive of response to gefitinib Mok TS, et al. N Engl J Med. 2009;361:247-257.